The Epidemiology Branch is conducting a number of birth defect studies in collaboration with the Health Research Board and Trinity College, Dublin, Ireland. The main objective of these studies is to determine the relationship between folate and birth defects. The birth defects studied to date are neural tube defects (NTDs), oral clefts, congenital heart defects,Down syndrome and omphalocele. These studies focus on biochemical factors in the area of folate metabolism, and on genetic mutations in folate related genes associated with birth defects. In the past we have shown that elevated homocysteine is a risk factor for NTDs, that a mutation in the methylenetetrahydrofolate reductase (MTHFR) gene 677C->T is a risk factor for NTDs, and that a small dose of folic acid (100-200 micrograms) can raise red cell folate to levels that can prevent a fifth to almost a half of NTDs. We have shown that methylenetetrahydrofolate reductase (MTHFD), an important gene in the production of purine and pyrimidine for DNA synthesis in a risk factor for NTDs. Mothers who have the R653Q variant of this gene are at increased risk of having a child with an NTD. This past year, we have expanded our work on MTHFD, showing that the R653Q variant is a risk factor for severe abruptio placentae and for unexplained second trimester pregnancy loss. We have also published a report showing that an important gene risk factor for NTDs, MTHFR C677T, is also a risk factor for omphalocele. We have explored other genes that have been proposed to be risk factors for NTDs, showing that they are not risk factors in our large population of genetically homogeneous Irish families.